Review

Synthse

Recommendations for the management of

dyslipidemia and the prevention of cardiovascular
disease: 2003 update
Jacques Genest, Jiri Frohlich, George Fodor, Ruth McPherson (the Working Group
on Hypercholesterolemia and Other Dyslipidemias)
This article appears online only and is an appendix to CMAJ 2003;168(9):921-4.

linical practice guidelines require continual reassessment in response to new information and
changes in the pattern of disease. Challenges in
Canada, as in all industrialized countries, include the increasing size of the elderly population and the rising
prevalence of obesity and diabetes mellitus. More than
20% of Canadians will be over 65 years of age by 2011; the
fastest-growing age group is those over 80 years, expected
to double by 2026 to 1.9 million.1 Obesity, particularly abdominal adiposity, is associated with an increased prevalence of diabetes, hypertension and other features of the
metabolic syndrome (hypertriglyceridemia, low levels of
high-density lipoprotein cholesterol [HDL-C] and insulin
resistance) as well as increases in a number of proinflammatory markers, including C-reactive protein and interleukin-6. Currently, 31% of Canadian adults are obese
(defined as a body mass index greater than 27 kg/m2).
Type 2 diabetes is a major risk factor for coronary artery
disease, and its prevalence is reaching epidemic proportions.2 The current incidence of new cases of diabetes is
estimated at 60 000 per year, and the prevalence is projected to increase from 1.5 million in 1998 to 3 million in
2010.3 The First Nations population, with a risk of diabetes 3 to 5 times higher than that of the general Canadian
population, is at particular risk.4
Because of the burden of cardiovascular disease and the
high rate of death from out-of-hospital acute myocardial
infarction, preventive measures are essential in order to
reduce health care costs and improve the health of Canadians. The Working Group on Hypercholesterolemia
and other Dyslipidemias issued recommendations for the
management of dyslipidemias in Canada in 2000.5 Since
the publication of these Canadian guidelines and of the
US National Cholesterol Education Program Adult
Treatment Panel-III (NCEP ATP-III) report,6 in 2001,
the findings from several important clinical trials have
been reported, including those from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
(MIRACL) Study,7 the Veterans Affairs High-Density

Lipoprotein Intervention Trial (VA-HIT)8 and the Heart

Protection Study (HPS).9 As a result, the working group
was reconvened to assess this new information and to address the increasing prevalence of the metabolic syndrome and its effect on the risk of cardiovascular disease.
The main purpose of the recommendations is to provide
primary care physicians and internists with a tool for evaluating a patients risk of coronary artery disease as part of
a routine health assessment.
The updated recommendations have been simplified
and include 3 levels of risk of coronary artery disease
(high, moderate and low) and 2 treatment targets (the lowdensity lipoprotein cholesterol [LDL-C] level and the total cholesterol:HDL-C ratio). The US NCEP ATP-III
guidelines also provide 3 levels of risk based on the Framingham Study equation but, in contrast to the Canadian
guidelines, recommend the use of non-HDL-C levels (i.e.,
the sum of very-low-density lipoprotein cholesterol
[VLDL-C] and LDL-C levels) as its secondary therapeutic
goal, especially in patients with features of the metabolic
syndrome. Because the total cholesterol:HDL-C ratio is a
more sensitive and specific index of cardiovascular risk
than total cholesterol, the working group has chosen this
simple lipid ratio as a secondary goal of therapy. Topics
specifically addressed in the revised guidelines include the
management of patients at high risk of coronary artery disease who have an LDL-C level at target (2.5 mmol/L), the
management of patients who have combined dyslipidemia
and low HDL-C levels, and the noninvasive assessment of
cardiovascular disease and other risk factors, including the
metabolic syndrome 10 and levels of apolipoprotein B,
lipoprotein(a), homocysteine and C-reactive protein.
The revised guidelines attempt to harmonize cardiovascular risk assessment across North America using the
Framingham Study equations published in the NCEP
ATP-III report.6 In addition, the guidelines will provide a
background recommendation for Canadian specialty organizations such as the Canadian Hypertension Society, the
Canadian Diabetes Association, the Dietitians of Canada
CMAJ OCT. 28, 2003; 169 (9)
2003 Canadian Medical Association or its licensors

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Genest et al

and the Canadian Society of Atherosclerosis, Thrombosis

and Vascular Biology. The guidelines were reviewed by 2
expert panels that included recognized specialists in the areas of cardiovascular disease prevention, lipid metabolism
and diabetes as well as primary care physicians. In addition,
several medical professional associations had an opportunity to review and comment on this document.

Global risk assessment

For the 2000 Canadian guidelines, the Framingham
Study risk equations used by the working group were those
published by Grundy and colleagues.11 The NCEP ATPIII used an adaptation of Framingham data based on the estimated 10-year risk of hard cardiac endpoints. These include death from coronary artery disease and nonfatal
myocardial infarction. The NCEP ATP-III risk estimate
tables also adjust certain risk factors (e.g., total cholesterol
level and smoking status) for age and correct for the effect
of treatment on blood pressure measurement. This represents a refinement to the previously published risk assessment tables. For these reasons and in order to harmonize
cardiovascular risk assessment across North America, the
working group has used the NCEP ATP-III risk estimation algorithm6 in the updated recommendations. The
presence of diabetes is generally considered as a coronary
artery disease risk equivalent. The Canadian Diabetes Association considers that an adult diabetic patient should be
categorized as being at high risk. The working group
agrees that a young patient whose diabetes is controlled by
diet may still have a relatively low 10-year risk estimate, but
the long-term risk is very high and should be considered
when making treatment decisions.

Risk assessment
A given patients 10-year risk of coronary artery disease
can be estimated using the model in Table 1.

Screening
Routinely screen men over 40 years of age and women
who are postmenopausal or over 50 years of age. In addition, screen those with: diabetes mellitus; risk factors such
as hypertension, smoking or abdominal obesity; a strong
family history of premature cardiovascular disease; manifestations of hyperlipidemia (e.g., xanthelasma, xanthoma or
arcus corneae); or evidence of symptomatic or asymptomatic atherosclerosis.
Patients of any age may be screened at the discretion of the
physician, particularly when lifestyle changes are indicated.

Risk categories
Three categories of risk are recognized (Table 2). Patients at high risk include those with established coronary
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JAMC 28 OCT. 2003; 169 (9)

artery disease, cerebrovascular disease or peripheral arterial

disease; patients with chronic kidney disease; adult diabetic
patients; and asymptomatic patients in whom the 10-year
risk of death from coronary artery disease or nonfatal myocardial infarction is 20% or higher. Patients at moderate, or
intermediate, risk include those with a 10-year risk greater
than 10% but less than 20%.
The working group no longer recommends a discrete
target for the plasma (or serum) triglyceride level. An
optimal plasma triglyceride concentration is less than
1.7 mmol/L. Achievement of the target total cholesterol:HDL-C ratio will require treatment of significantly
elevated triglyceride levels. Severe hypertriglyceridemia
(triglyceride level greater than 10.0 mmol/L) should also
be treated since it is a risk factor for pancreatitis. The preferred drug for the treatment of hypertriglyceridemia, in
combination with diet and lifestyle changes, is a fibric acid
derivative or niacin. In refractory cases, the addition of
oils rich in omega-3 fatty acids derived from fish may be
very effective.

Factors influencing risk assessment

Metabolic syndrome
The clustering of cardiovascular risk factors is recognized as being an important health issue. The metabolic
syndrome is defined in qualitative terms and encompasses
abdominal obesity, insulin resistance, elevated plasma
triglyceride levels, low HDL-C levels and high blood pressure (Table 3).
Role of abdominal obesity

Epidemiologic data have shown that abdominal obesity

is associated with small, dense LDL particles, elevated
apolipoprotein B levels, reduced plasma HDL-C levels,
insulin resistance and hypertension. These features are
observed in about half of patients with the metabolic syndrome. Adipose tissue synthesizes and secretes a variety of
proteins, with important systemic effects. These proteins
are collectively referred to as adipocytokines and include
leptin, tumour necrosis factor, adiponectin, resistin, adipsin, angiotensinogen, plasminogen activator inhibitor-1
and C-reactive protein. Secretion of these cytokines and
global changes in insulin sensitivity are in part contingent
on adipose tissue mass and distribution. Although visceral
fat accounts for only about 10% of total body fat, this
depot is most strongly related to insulin resistance and
dyslipidemia. Visceral adipocytes demonstrate higher
lipolytic activity and release free fatty acids directly to the
liver through the portal circulation. Waist circumference
is a useful estimate of abdominal obesity and indicator of
cardiovascular risk. The NCEP ATP-III has used cut-off
values of waist circumference of 102 cm for men and
88 cm for women.

Updated recommendations for managing dyslipidemias

Table 1: Model for estimating the 10-year risk of coronary artery disease in a patient without diabetes mellitus or clinically
11
evident cardiovascular disease, using data from the Framingham Heart Study
MEN
Risk factor

WOMEN
Risk points

Age group, yr
2034
3539
4044
4549
5054
5559
6064
6569
7074
7579
Total cholesterol
level, mmol/L
< 4.14
4.155.19
5.206.19
6.207.20
7.21
Smoker
No
Yes

< 120
120129
130139
140159
160
Total risk points
<0
04
56
7
8
9
10
11
12
13
14
15
16
17

Age group, yr

Total cholesterol
level, mmol/L

2039

4049

5059

6069

7079

0
4
7
9
11

0
3
5
6
8

0
2
3
4
5

0
1
1
2
3

0
0
0
1
1

< 4.14
4.155.19
5.206.19
6.207.20
7.21

0
8

0
5

0
3

0
1

0
1

Smoker
No
Yes

7
3
0
3
6
8
10
12
14
16
Age group, yr
2039

4049

5059

6069

7079

0
4
8
11
13

0
3
6
8
10

0
2
4
5
7

0
1
2
3
4

0
1
1
2
2

0
9

0
7

0
4

0
2

0
1

HDL-C level,
mmol/L
1.55
1.301.54
1.041.29
< 1.04

1
0
1
2
Untreated

Treated

0
0
1
1
2

0
1
2
2
3

10-year risk, %
<1
1
2
3
4
5
6
8
10
12
16
20
25
30

Risk points

Age group, yr
2034
3539
4044
4549
5054
5559
6064
6569
7074
7579

9
4
0
3
6
8
10
11
12
13

HDL-C level,
mmol/L
1.55
1.301.54
1.041.29
< 1.04
Systolic blood
pressure, mm Hg

Risk factor

Systolic blood
pressure, mm Hg
< 120
120129
130139
140159
160
Total risk points

10-year risk:
_______ %

1
0
1
2
Untreated

Treated

0
1
2
3
4

0
3
4
5
6

10-year risk, %

<9
912
1314
15
16
17
18
19
20
21
22
23
24
25

CMAJ OCT. 28, 2003; 169 (9)

<1
1
2
3
4
5
6
8
11
14
17
22
27
30

10-year risk:
_______ %

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Genest et al

Apolipoprotein B

Lipoprotein(a)

Each of the atherogenic particles namely, VLDL,

intermediate-density lipoprotein, LDL and lipoprotein(a)
contain 1 molecule of apolipoprotein B. Thus, the serum
concentration of apolipoprotein B reflects the total number
of these particles. Four recent prospective studies showed the
apolipoprotein B concentration to be a better estimate of the
risk of vascular events than the LDL-C level.12 Risk is highest in people with an apolipoprotein B level of more than
1.2 g/L and a triglyceride level of more than 1.5 mmol/L.
This profile is often associated with the presence of smaller,
denser and more atherogenic LDL particles. Increased
apolipoprotein B levels and high triglyceride concentrations
are prevalent in patients with the metabolic syndrome and
type 2 diabetes. Apolipoprotein B may be of particular value
in assessing the adequacy of statin treatment. As shown in a
number of statin trials, apolipoprotein B levels during treatment relate more strongly to clinical outcomes than do
LDL-C levels during treatment.12 Another advantage of
measuring apolipoprotein B is that fasting samples are not
required. In addition, Canadian population values have been
established, apolipoprotein B has been standardized, and
most laboratories have the equipment and expertise to measure it. For the Canadian population, an apolipoprotein B
level of 0.9 g/L is about the 20th percentile, 1.05 g/L the
50th percentile and 1.2 g/L the 75th percentile.
In summary, apolipoprotein B concentration can be
used to identify the risk category of patients with moderate
hypertriglyceridemia and is a useful indicator of the adequacy of lowering the number of atherogenic particles.
Plasma apolipoprotein B measurement may be of particular
utility in determining cardiovascular risk and adequacy of
treatment in people who have the metabolic syndrome. An
optimal level of apolipoprotein B in a patient at high risk of
coronary artery disease is less than 0.9 g/L.

Lipoprotein(a) is an LDL particle in which apolipoprotein B is attached to apolipoprotein(a) protein by a disulfide bridge. The apolipoprotein(a) moiety has structural
homology to plasminogen and may compete with plasminogen for binding to fibrin and plasminogen receptors
on endothelial cells and thus impair fibrinolysis. Lipoprotein(a) has been identified as a potent predictor of premature atherosclerosis in most of the large prospective studies.13,14 Elevated lipoprotein(a) levels occur in 15%20% of
people with premature atherosclerosis,15 and most studies
support lipoprotein(a) as an independent risk factor for
coronary artery disease. A meta-analysis of 18 populationbased cohorts indicated that the combined risk ratio for
those in the upper versus lower tertile of the population
distribution for lipoprotein(a) was 1.7.16 There are accumulating data suggesting that the atherogenicity of lipoprotein(a) is aggravated by other risk factors.16 Subgroup
and post-ad-hoc analysis of published studies suggests that
plasma lipoprotein(a) levels are no longer predictors of
coronary artery disease once the LDL-C level has been
markedly reduced. 16 Hopkins and associates 17 demonstrated a much greater effect of lipoprotein(a) on coronary
artery disease risk in people with an elevated total cholesterol:HDL-C ratio or other risk factors for coronary
artery disease than in people without such risk factors. The
mechanism by which lipoprotein(a) interacts with plasma
lipoproteins to increase the risk of atherosclerosis is unknown. Lipoprotein(a) may facilitate the proatherogenic
effects of LDL. Lipoprotein(a) concentrations are determined by a single gene and are not responsive to dietary
therapy. Measurement of lipoprotein(a) is not routinely
recommended as part of lipid screening but may be useful
in determining coronary artery disease risk in patients at
moderate risk who have a family history of early coronary
artery disease. A lipoprotein(a) concentration greater than
30 mg/dL in a patient who has a total cholesterol:HDL-C
ratio greater than 5.5 or other major risk factors may indicate the need for earlier and more intensive therapy to
lower the LDL-C level.

Table 2: Risk categories and target lipid levels

Target level
Risk category
High*
(10-year risk of coronary artery
disease 20%, or history of
diabetes mellitus or any
atherosclerotic disease)
Moderate
(10-year risk 11%19%)
Low
(10-year risk 10%)

LDL-C level,
mmol/L

Total cholesterol:
HDL-C ratio

Table 3: Clinical identification of the metabolic syndrome*

Risk factor
< 2.5 and

< 4.0

< 3.5 and

< 5.0

< 4.5 and

< 6.0

Note: LDL-C = low-density lipoprotein cholesterol.

*Apolipoprotein B can be used as an alternative measurement, particularly for follow-up of
patients treated with statins. An optimal level of apolipoprotein B in a patient at high risk is
< 0.9 g/L, in a patient at moderate risk < 1.05 g/L and in a patient at low risk < 1.2 g/L.
Includes patients with chronic kidney disease and those undergoing long-term dialysis.
In the very low risk stratum, treatment may be deferred if the 10-year estimate of
cardiovascular disease is < 5% and the LDL-C level is < 5.0 mmol/L.

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Abdominal obesity
Men
Women

Defining level
Waist circumference > 102 cm
Waist circumference > 88 cm
1.7 mmol/L

Triglyceride level
HDL-C level
Men
Women

< 1.0 mmol/L

< 1.3 mmol/L

Blood pressure
Fasting glucose level

130/85 mm Hg
6.27.0 mmol/L

*Criteria: 3 or more of the risk factors.

Updated recommendations for managing dyslipidemias

Homocysteine
Elevated plasma concentrations of homocysteine are a
strong predictor of adverse outcomes in patients with coronary artery disease and are prevalent in patients with renal
impairment and those with cardiovascular disease. Several
cross-sectional and retrospective studies have demonstrated
a role for elevated homocysteine levels in determining
coronary artery disease risk.18 Normal plasma homocysteine levels range between 5 and 15 mol/L, and, although
hyperhomocysteinemia refers to levels between 16 and
100 mol/L, even mildly elevated levels (greater than 10
15 mol/L) are associated with an increased risk of cardiovascular disease.19 Plasma homocysteine levels above the
90th to 95th percentile are associated with an increased risk
of cardiovascular disease, stroke and deep vein thrombosis
(odds ratio 1.7).20
Randomized controlled trials of the effect of lowering
homocysteine levels on cardiovascular end points are under
way and should be completed by 20042006. These trials
involve a fixed dose of folic acid (12 mg) and vitamin B12
(1 mg). A treat-to-target (9.0 mol/L) homocysteinelowering trial is still needed. The position of the working
group, the Canadian Cardiovascular Society, the American
Heart Association and the Heart and Stroke Foundation of
Canada is that there is insufficient evidence to warrant
broad homocysteine screening until these ongoing clinical
trials show that vitamin supplementation to lower homocysteine levels decreases cardiovascular risk. However,
there may be a specific indication for treatment with folic
acid and vitamin B12 in patients undergoing percutaneous
coronary revascularization.2123 Similarly, the treatment of
homocysteine concentrations greater than 10 mol/L with
folic acid and vitamins B12 and B6 may be warranted in
high-risk patients who have renal or cardiovascular disease.

High-sensitivity C-reactive protein

The acute-phase concentration of C-reactive protein is a
very sensitive, objective marker of inflammation, and the
ability to measure C-reactive protein at very low concentrations may permit identification of asymptomatic patients
at risk of acute coronary events. Recent data from the
Womens Health Study24 suggest that measurement of
high-sensitivity C-reactive protein adds prognostic information to that provided by the Framingham Study risk
score in terms of predicting coronary artery disease events.
An elevated level of high-sensitivity C-reactive protein is
associated with abdominal obesity and is another component of the metabolic syndrome.25 In several studies, baseline levels in the upper quartile of the population distribution in people without cardiovascular disease were
associated with a 3- to 4-fold increased incidence of subsequent coronary events.24,26,27 Available data also suggest that
measurement of the high-sensitivity C-reactive protein
level may help target treatment to the population at risk;28

this is relevant, since about half of all coronary events occur

in people without marked LDL-C elevations.
The working group does not currently provide firm recommendations regarding the use of the high-sensitivity Creactive protein measurement in risk assessment. However,
measurement may be clinically useful in identifying people
who are at a higher risk of cardiovascular disease than that
predicted by a global risk assessment, in particular those
with a calculated 10-year risk between 10% and 20%. Fasting is not a requirement for measurement of high-sensitivity C-reactive protein. However, measurement should not
be done during any acute illness and is not an index of cardiovascular risk in patients with chronic inflammatory conditions. Duplicate measurements, optimally 2 weeks apart,
are recommended. The lower number should be considered the reliable value. Use of the high-sensitivity assay is
essential when measurement of C-reactive protein is used
for risk assessment; in most provinces, patients will be
asked to pay for the analysis. Low risk is defined as a level
less than 1 mg/mL, average risk as 1.03.0 mg/L and high
risk as 3.010 mg/L. If the concentration is greater than
10 mg/L, the test should be repeated and the patient examined for sources of infection or inflammation.29

Genetic risk
The genetic contribution to the risk of coronary artery
disease cannot be quantified reliably on the basis of current
knowledge. Familial aggregation can be primarily genetic
(as seen in familial hypercholesterolemia) or can reflect a
genetic predisposition to dyslipidemia, hypertension, diabetes, hypercoagulability or other cardiovascular risk factors. Shared household effect (diet, sedentary lifestyle) can
also produce familial clustering of coronary artery disease.
Despite these caveats, premature coronary artery disease
(presenting before 55 years of age in men and before 65
years in women) in a first-degree relative (parent, sibling or
child) should alert the clinician to increase the risk category
to a higher level. When a family history of coronary artery
disease can be ascertained unambiguously, the risk for firstdegree relatives is increased by 1.7 to 2.0. This should be
taken into account in risk stratification and may increase
the risk category in individual patients.

Hormone replacement therapy

New information from the Womens Health Initiative21
and the Heart Estrogen/Progestin Replacement Study30,31 has
demonstrated that oral hormone replacement therapy (HRT)
does not reduce and may increase cardiovascular disease risk.
Most of the data available to make clinical recommendations
are based on standard doses of orally administered conjugated
equine estrogen plus medroxyprogesterone acetate. Information regarding the possible cardiovascular risks and benefits of
transdermal use of estrogen, other progestins or selective estrogen receptor modulators is incomplete.
CMAJ OCT. 28, 2003; 169 (9)

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Genest et al

Primary prevention

HRT should not be initiated for the primary prevention of cardiovascular disease.
Initiation and continuation of HRT should be based on
established noncoronary benefits and risks, possible
coronary risks and patient preference.
Unless otherwise indicated for osteoporosis treatment
or severe menopausal symptoms, efforts should be
made to stop or taper HRT in women over the age of
55 years who have been treated with HRT for more
than 5 years.
Secondary prevention

HRT should not be initiated for the secondary prevention of cardiovascular disease.
If a woman experiences an acute cardiovascular event or
is scheduled for coronary artery bypass grafting, a percutaneous coronary intervention or other surgery, consideration should be given to stopping HRT.

Findings from new trials

The Heart Protection Study9 was a landmark study involving 20 556 men and women aged 4080 years who
had a total cholesterol level above 3.5 mmol/L and were
at high risk of coronary artery disease. The study subjects
included patients with established coronary artery disease, those who had had a myocardial infarction, those
with peripheral or cerebral vascular disease, and patients
with diabetes or hypertension or both. The study added
to a recent body of data demonstrating no cardiovascular
benefit with oral antioxidant vitamin therapy. The main
finding was that the use of simvastatin (40 mg/d) decreased the death rate by 13% and reduced the rate of all
cardiovascular end points by 24%. With adjustment for
lack of compliance in the simvastatin group and for patients in the placebo group who took a statin, the actual
effect may be increased by 1.5-fold. Predefined subgroup
analysis showed benefit in men and in women, in young
and old, and in patients with and without established disease. More important, benefits extended across all ranges
of total cholesterol and LDL-C levels. Indeed, subjects
with a baseline LDL-C level of less than 2.6 mmol/L
demonstrated the same magnitude of risk reduction as
those with higher LDL-C levels. In light of these data,
the working group now suggests that people at high risk
of coronary artery disease be treated with the equivalent
of 40 mg/d of simvastatin and that the minimum target
of therapy be an LDL-C level of less than 2.5 mmol/L
and a total cholesterol:HDL-C ratio of less than 4.0.
Controversy still exists as to the optimal LDL-C level in
people at high risk of a cardiovascular event. Large clinical trials are under way to examine clinical outcomes in
patients with cardiovascular disease treated to reach a
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JAMC 28 OCT. 2003; 169 (9)

target LDL-C level of less than 1.8 mmol/L versus the

conventional target of less than 2.6 mmol/L. Until the
results of these trials are published, available evidence
suggests that a patient at high risk should be treated with
the equivalent of 40 mg/d of simvastatin and that an
LDL-C level of less than 2.5 mmol/L should be
achieved.
In the MIRACL Study,7 atorvastatin (80 mg/d) was
compared with best treatment and angioplasty in patients
with stable coronary artery disease. There was a reduction
in the rate of cardiovascular events of 16%, most of the
benefit being attributable to admission to hospital because
of recurrent angina. The study showed that high-dose
atorvastatin is safe and may acutely reduce the rate of cardiovascular events. The VA-HIT investigators8 examined
patients with established coronary artery disease and a
normal LDL-C level but a reduced HDL-C level. The
use of gemfibrozil (1200 mg/d) was associated with a 22%
decrease in the rate of recurrent coronary events. The Diabetes Atherosclerosis Intervention Study32 was an angiographic trial of fenofibrate in patients with diabetes and
dyslipidemia. Although the change in the prespecified primary end point did not reach statistical significance, one
angiographic measure of coronary disease progression was
reduced with fenofibrate. A reduction in clinical end
points was also noted, although the study was not powered to evaluate clinical events. The HDL-Atherosclerosis
Treatment Study33 was an angiographic trial of low-dose
simvastatin (1020 mg/d) plus niacin (1500 mg/d) with or
without antioxidant vitamins or placebo. In this small trial,
there was angiographic reduction of coronary artery disease and a 90% reduction in the rate of major cardiovascular events with the combination treatment. Antioxidants
had no effect.
The Anglo-Scandinavian Cardiac Outcomes Trial34 investigators compared the effects of atorvastatin (10 mg)
versus placebo on the combined outcome of nonfatal
myocardial infarction (including silent myocardial infarction) and fatal coronary artery disease in 9000 hypertensive patients with total cholesterol levels of less than
6.5 mmol/L. These patients had other risk factors for
coronary artery disease but no evidence of pre-existing
coronary artery disease. The study was stopped after
3 years because of significant apparent benefit in the
treatment group. There was a reduction of 36% in the
rates of fatal and nonfatal myocardial infarction, together
with significant reductions in the rates of stroke (27%), all
cardiovascular events and procedures (21%) and total
coronary events (29%). This study provides strong support for statin therapy in patients at high risk in the primary prevention category.
These studies provide new information relevant to risk
stratification algorithms, the target LDL-C levels in patients at high risk, the use of high-dose statin therapy and
better recommendations for managing people at high risk
who have low HDL-C levels.

Updated recommendations for managing dyslipidemias

Diagnosis of asymptomatic atherosclerosis

Atherosclerosis may be detected and the diagnosis of cardiovascular disease confirmed using the following methods:
Recommended: physical examination; anklebrachial index
Possibly useful in subjects at moderate risk: carotid ultrasonography (may detect clinically unapparent atherosclerosis); electrocardiography; graded exercise testing
in men over 40 years who have risk factors
Not currently recommended, based on available evidence: flowmediated vasodilatation, plethysmography, arterial compliance; electron beam CT scanning; MRI scanning; intravascular ultrasonography
The anklebrachial index is the ratio of systolic blood
pressure in the dorsalis pedis or posterior tibial artery to
the systolic blood pressure in the brachial artery. Requirements include a blood pressure cuff and Doppler ultrasonic sensor. Measurement of the anklebrachial index can
be of particular utility in assessing asymptomatic vascular
disease in middle-aged or elderly patients with other risk
factors. An index of less than 0.90 in either leg is a reliable
indicator of peripheral vascular disease, with a sensitivity
of 90% and specificity of 98% for detecting stenosis of
greater than 50%. Symptomatic peripheral vascular disease is associated with a marked increase in the risk of cardiovascular disease.35
Carotid B-mode ultrasonography can also be of use in assessing asymptomatic atherosclerosis. Most of the published
literature pertains to the measurement of intimalmedial
thickness. Measurements are obtained bilaterally on the distal 1 cm of the common carotid, the carotid bifurcation and
the proximal 1 cm of the internal carotid. Among asymptomatic people over the age of 50, several studies have shown
up to a 5-fold increase in the risk of cardiovascular disease
for those with increased intimalmedial thickness.3638 Measurement of intimalmedial thickness is a useful tool in cardiovascular risk assessment but is not yet a standard measure
in routine carotid ultrasonography. Although these measurements are not routinely available, patients with evidence
of nonstenotic carotid lesions or sessile plaque on routine
carotid Doppler ultrasonography similarly are candidates
for secondary prevention strategies. The degree of stenosis
required for a high-risk approach has not been determined
in clinical trials.
Exercise stress testing in asymptomatic men over the age
of 40 years can also be useful in risk stratification. Gibbons
and coworkers39 studied 25 927 healthy men with a mean
age of 43 years. In this group of asymptomatic men, a positive stress test result was associated with a 21-fold increased
relative risk of coronary artery disease among those with no
risk factors and an 8- to 10-fold increase in relative risk
among those with risk factors. Earlier reports from the
Lipid Research Clinics Coronary Primary Prevention
Trial40 and the Multiple Risk Factor Intervention Trial
(MRFIT)41 also showed that a positive result of exercise
stress testing strongly predicted risk of coronary artery dis-

ease. Thus, a positive exercise stress test result (1 mm or

more of ST-segment depression within 6 minutes on the
Bruce protocol) can move a middle-aged man from the
moderate-risk to the high-risk secondary prevention category. In contrast, a negative stress test result and good exercise tolerance (greater than 8 metabolic equivalents) carries a good prognosis in this group. Fewer data are available
to support exercise stress testing as part of risk assessment
for women, although there may be a role for nuclear perfusion scanning in the presence of risk factors and possible
angina symptoms.

Treatment
Diet
Although there have been significant improvements in
dietary composition in the past 4 decades, particularly decreases in intake of saturated fat and cholesterol, these gains
have been partly offset by a continuing increase in the
prevalence of obesity. Dietary intervention should be part of
a strategy of lifestyle changes aimed at increasing exercise,
increasing fruit and vegetable intake and increasing the proportion of mono- and polyunsaturated fats in the diet while
decreasing the proportion of saturated fats and trans-fatty
acids to less than 7% of total calories. An increase in the intake of omega-3 fatty acids from fish and plant sources is
also recommended. An important focus should be on decreasing energy consumption, in particular by reducing intake of refined carbohydrates and sugar to achieve and
maintain a body mass index of less than 25 kg/m2.

Medication
Target lipid levels

In people at high risk of coronary artery disease, treatment should be started immediately, concomitant with diet
and therapeutic lifestyle changes. The priority for treatment is reduction of the LDL-C level to less than
2.5 mmol/L and the total cholesterol:HDL-C ratio to less
than 4.0. In light of the new data from the Heart Protection Study,9 the working group recommends that people at
high risk be treated with the equivalent of 40 mg/d of simvastatin, with a minimum target level for LDL-C of
2.5 mmol/L. A summary of currently used lipid-lowering
medications is shown in Table 4.
Achievement of target LDL-C levels

Most patients, including those with the metabolic syndrome, diabetes and combined dyslipidemia, will be able to
achieve target LDL-C levels with statin monotherapy. A
substantial minority of patients will, however, require combination therapy with a bile acid sequestrant (cholestyramine or colestipol). New cholesterol absorption inhibitors
CMAJ OCT. 28, 2003; 169 (9)

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Genest et al

(ezetimibe) are available and are better tolerated than bile

acid sequestrants. These combinations are safe and can decrease LDL-C levels by an additional 10% to 20%.
Achievement of target total cholesterol:HDL-C ratio

Particularly for patients at high risk, the target total cholesterol:HDL-C ratio (less than 4.0) may be more difficult
to achieve than the target LDL-C levels. The following approaches are recommended.
Lifestyle therapy: For patients with hypertriglyceridemia,
intensify dietary therapy and exercise, with a focus on
weight loss and restriction of refined carbohydrate and alcohol. For patients with low HDL-C levels, increased aerobic exercise, increased intake of monounsaturated fats,
moderate alcohol intake (only if the triglyceride level is
within normal limits) and weight loss are beneficial.
Combination therapy: In patients with combined dyslipidemia and low HDL-C levels, the combination of a statin
with niacin is very effective and was reported to reduce cardiovascular events significantly in the HDL-Atherosclerosis
Treatment Study.33 Niacin is the only available agent that
significantly increases HDL-C concentrations. Side effects,
which may be significant, include flushing, dry skin and
gastrointestinal irritation. Niacin should be taken 2 to 3
times daily, after meals, and the dose should be increased
slowly. NSAIDS, including ASA, attenuate the vasodilatory
side effects in most patients. There is a small but significant
risk of hepatotoxic effects with niacinstatin treatment, and
transaminase levels should be monitored. Niacin may also
impair insulin sensitivity, and drug regimens may have to

Table 4: Current lipid-lowering medications

Drug
Statins
Atorvastatin (Lipitor)
Fluvastatin (Lescol)
Lovastatin (Mevacor)
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
Simvastatin (Zocor)
Resins (bile acid sequestrants)
Cholestyramine (Questran)
Colestipol (Colestid)
Cholesterol absorption inhibitors
Ezetimibe (Ezetrol)
Fibrates*
Bezafibrate (Bezalip)
Fenofibrate (Lipidil)
Gemfibrozil (Lopid)
Niacin
Nicotinic acid

Recommended daily dose

1080 mg
2080 mg
2080 mg
1040 mg
1040 mg
1080 mg
224 g
530 g
10 mg
400 mg
67200 mg
6001200 mg
13 g

*Avoid in patients with renal insufficiency. Do not use gemfibrozil in combination with statins.
Use with caution in patients with diabetes or glucose intolerance.

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JAMC 28 OCT. 2003; 169 (9)

be modified for patients with diabetes or impaired glucose

tolerance. For patients who do not tolerate or are not candidates for niacin therapy, a combination of a statin with a
fibrate may be used, with close patient follow-up. Fibrates
increase serum creatinine and homocysteine levels, and fibrates alone or statinfibrate combination therapy should
not be used in patients with renal impairment (or should be
used under carefully monitored conditions). In general, the
smallest available doses of both fibrate and statin are recommended for initial treatment. Available data suggest that
fenofibrate is reasonably safe in combination with either
simvastatin or pravastatin.42 Gemfibrozil is associated with a
higher risk of myotoxic effects and should not be used in
combination therapy. For patients with moderate hypertriglyceridemia, the addition of salmon oil (13 g three
times daily) to statin therapy is safe and may be useful in
lowering triglyceride levels and thus achieving the target
total cholesterol:HDL-C ratio.
Increase statin dose: For patients with low HDL-C levels
or mild hypertriglyceridemia (triglyceride level less than
5.0 mmol/L) the recommended target total cholesterol:
HDL-C ratio may often be achieved by a further increase in
statin dose even if the target LDL-C level has been reached.
Achievement of target triglyceride levels

Epidemiologic evidence suggests that the optimal

triglyceride level is less than 1.7 mmol/L.43,44 Current recommendations are to first implement and maintain lifestyle changes rather than to attempt to lower triglyceride
levels by pharmacologic means. Achievement of the target
total cholesterol:HDL-C ratio usually entails modification
of triglyceride levels when elevated. Severe hypertriglyceridemia poses a significant risk for pancreatitis, and patients with triglyceride levels of more than 6.0 mmol/L despite optimal lifestyle therapy require drug treatment.
Available options include a fibrate, niacin and salmon oil
supplementation.

Follow-up
Large-scale clinical trials such as the Heart Protection
Study9 have shown that the statin class of drugs is very well
tolerated. After drug therapy is started, plasma levels of
lipids and lipoprotein lipids are expected to reach a steady
state within 6 weeks. Long-term follow-up after the initial
titration period can be performed every 612 months.
More frequent monitoring of transaminases and creatinine
kinase is warranted in subjects receiving maximum doses of
medications and those receiving combination therapy (especially statins and fibrates).

Referrals
Physicians are often confronted with difficult cases, lack
of laboratory resources, unexplained atherosclerosis, ex-

Updated recommendations for managing dyslipidemias

tremes of lipoprotein disorders or a lack of response to

conventional therapies. In such cases, referral to a specialized centre may be warranted. Most medical schools in
Canada have specialized lipid clinics and the laboratory
backup for extensive testing. In extreme cases therapeutic
modalities such as extracorporeal LDL precipitation techniques are available. The working group recommends that
specialists in lipoprotein disorders in each province be
available for consultation for difficult cases.
Some patients may present with unexplained atherosclerosis. In these cases, the degree of atherosclerosis is not explained by conventional risk factors. The evaluation of such
patients should include measurement of concentrations of
apolipoprotein B, lipoprotein(a), homocysteine and highsensitivity C-reactive protein. Even in the presence of a
normal LDL-C level, such cases warrant treatment with
ASA and a statin if the total cholesterol level is greater than
3.5 mmol/L.

7.

8.
9.
10.
11.

12.
13.
14.

This article has been peer reviewed.

Dr. Genest is with the Royal Victoria Hospital, McGill University, Montral, Que.
Dr. Frohlich is with St. Paul's Hospital, University of British Columbia, Vancouver, BC. Drs. Fodor and McPherson are with the University of Ottawa Heart Institute, Ottawa, Ont.
Competing interests: The authors did not receive financial support from pharmaceutical companies for their work in developing these recommendations and producing
this report. All have received speaker fees from various drug companies, including
those that manufacture drugs used to treat dyslipidemia and cardiovascular disease;
Drs. Genest, Frohlich and McPherson have been members of advisory boards of various drug companies; and Drs. Fodor, Frohlich and McPherson have received travel
expenses from one or more drug companies to attend scientific meetings.
Contributors: Each of the authors contributed substantially to the drafting and revising of the article. All approved the final version submitted for publication.

15.
16.
17.
18.
19.
20.
21.

Acknowledgements: We acknowledge the following for their advice and comments on the recommendations: Dr. Jean Bergeron, Laval, Que.; Dr. Ross Feldman, Robarts Research Institute, London, Ont.; Dr. Milan Gupta, Hamilton, Ont.;
Dr. Lawrence Leiter, University of Toronto, Toronto, Ont.; Dr. Garry Lewis,
University of Toronto, Toronto, Ont.; Dr. G.B. John Mancini, University of
British Columbia, Vancouver, BC; and Dr. Bruce Sussex, Memorial University,
St. Johns, Nfld. We also thank Dr. Helen Stokes, University of Ottawa, Ottawa,
Ont., and Kristi Adamo and Penlope Turton, Ottawa Heart Institute, Ottawa,
Ont., for their help in writing the manuscript.

23.

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Correspondence to: Dr. Jacques Genest, Division of Cardiology,

McGill University Health Centre, Royal Victoria Hospital,
687 Pine Ave. W, Montral QC H3A 1A1; fax 514 843-2813;
jacques.genest@muhc.mcgill.ca